December 2011

December 26, 2011

In today’s new issue of JCB, Hégarat et al. describe how the Aurora family of protein kinases regulates chromosome and microtubule dynamics in mitosis. Cells lacking either Aurora A or Aurora B fail to properly align their chromosomes on the mitotic spindle, resulting in chromosome mis-segregations. As described in this summary, cells lacking Aurora A AND Aurora B, on the other hand, fail to depolymerize spindle microtubules in anaphase, preventing sister chromatid separation.

Schmidt et al. describe a signaling pathway that helps embed acetylcholine receptors in the post-synaptic membrane of neuromuscular junctions. Neuregulin signaling molecules bind to their ErbB receptors and induce the phosphorylation of a post-synaptic scaffold protein called alpha-dystrobrevin1, which stabilizes acetylcholine receptors at the post-synapse to maintain proper synaptic neurotranmission. As explained in this week’s In Focus, the signaling pathway seems to particularly affect acetylcholine receptors that have undergone a round of endocytic recycling, though why this population of receptors behaves differently isn’t clear. Meanwhile, Baez et al. describe how cytoplasmic RNA granules regulate post-synaptic remodeling. The researchers identify S-foci, which contain the translational repressor Smaug1 and which regulate the local translation of mRNAs encoding proteins (e.g. CaMKinaseII) in response to NMDA receptor stimulation.

Emond et al. reveal a new way for cells to adhere to each other. Though classical cadherins like E- and N-cadherin are known to mediate intercellular adhesion, the role of the related protocadherin proteins in holding cells together is much less clear. Emond et al. find that Protocadherin-19 becomes adhesive when it forms a complex with N-cadherin, so that it forms homophilic adhesions between neighboring cells. N-cadherin switches on Protocadherin-19’s adhesive properties, but it doesn’t mediate the intercellular adhesion itself. More here.

Sideridou et al. report that Cdc6, a protein that permits cells to replicate their DNA, also induces epithelial to mesenchymal transitions by shutting down the expression of E-cadherin. Cdc6 overexpression may therefore aid the progression of cancer by stimulating both DNA synthesis and metastasis. You can find a longer summary here.

And Nekrasova et al. reveal that the two types of cadherin molecules that assemble into desmosomal adhesions are transported to the plasma membrane by two distinct kinesin motors. You can learn more in this month’sbiosights, in which senior author Kathleen Green explains why using two independent transport mechanisms to build desmosomes might allow cells to tailor the strength of their adhesions during development and disease.

That’s all we have time for today, but you can find lots of other interesting papers in today’s new issue by visiting the table of contents here.

December 12, 2011

In today’s new issue of JCB, Gong et al. describe how a protein called Fsp27 promotes the growth of lipid droplets in fat-storing adipocytes. Fsp27 localizes to the site where neighboring droplets contact each other, and facilitates the transfer of lipids from the smaller to the larger droplet. More in this summary. Meanwhile, de Saint-Jean et al. describe how a protein called Osh4p exchanges sterols and phosphatidylinositol-4-phosphate between organelles in order to set up a sterol gradient across the different organelles of the secretory pathway. Tim Levine provides a comment on this surprising finding.

Bruns et al. identify a novel membrane-bound compartment in yeast called CUPS. This “Compartment for Unconventional Protein Secretion” contains many of the proteins required to deliver the Acyl-CoA-binding protein Acb1 to the surface of starving budding yeast via a recently-discovered pathway that sidesteps the usual secretory route through the ER and Golgi apparatus. You can learn more about the proteins that localize to CUPS, and how the organelle compares to similar compartments in the autophagy pathway, in this summary article.

And Garcia et al. reveal that the shape of septin filaments can be modulated by the incorporation of different septin subunits and by septin phosphorylation. Septins are a conserved family of GTPases that hetero-oligomerize into filamentous structures in order to control a variety of cellular processes, including budding yeast cytokinesis, where septins form an organized collar around the bud neck. Complexes containing the septin Cdc11 assemble into long, straight rods, but Garcia et al. find that substituting another septin, Shs1, in place of Cdc11 drives the formation of ring-shaped structures. Moreover, the phosphorylation of Shs1 can promote the assembly of septins into a gauze-like meshwork. Read more about how this all relates to septins’ functions at the yeast bud neck in this week’s In Focus.

Yamaguchi et al. perform some beautiful in vivo imaging to investigate how apoptosis contributes to neural tube closure in mouse embryonic brains (summary here) and Janes et al. examine the crosstalk between different subclasses of the Eph receptor tyrosine kinase family. This latter paper is covered in more detail in this month’sbiobytes podcast, in which you can also hear Vania Braga describe her lab’s recent paper explaining how the cell junction protein Ajuba regulates the Rac GTPase at intercellular contacts. You can listen below or subscribe in iTunes.

That’s all for today, but don’t forget to check out all the other great papers published in today’s new issue. You can find them all on our table of contents.

December 06, 2011

Co-chairs Claudio Joazeiro (The Scripps Research Institute) and Frauke Melchior (University of Heidelberg) put together a minisymposium on the third day of ASCB 2011 that nicely highlighted the diversity of cellular functions performed by ubiquitin and ubiquitin-like proteins.

Ubiquitin is best known for its role in protein degradation when E3 ubiquitin ligases tag proteins with ubiquitin in order to target them to the proteasome. But, as Joazeiro described in his opening talk, individual E3 ligases can take part in very specific degradation pathways, a fact exemplified by Listerin, an E3 ligase whose mutation in mice causes motor neuron degeneration. Joazeiro showed that the yeast homolog of Listerin, Ltn1, is involved in a type of protein degradation linked to an mRNA quality control pathway called non-stop mRNA decay. This pathway rids cells of mRNAs that lack a proper stop codon, but an abnormal polypeptide is always produced before the mRNA can be eliminated. Joazeiro showed that Ltn1 associates with ribosomes and targets for destruction the proteins produced from non-stop mRNAs.

Probably the second-best known role for ubiquitination is in cell signaling. Fumiyo Ikeda (IMBA, Vienna) presented data from her recent paper describing how SHARPIN - a component of the Linear Ubiquitin Chain Assembly Complex (LUBAC) - regulates two signaling pathways. SHARPIN promotes NFkappaB signaling by mediating the ubiquitination of and NFkappaB regulator called NEMO, and it also inhibits cell death by restricting apoptotic signaling through the death domain-containing protein FADD. SHARPIN-deficient mice therefore suffer from increased apoptosis and inflammation.

The following two talks dealt with some less-appreciated roles of ubiquitination. Corinne Albiges-Rizo (Institut Albert Bonniot, Grenoble) discussed how ubiquitination of an integrin-binding protein helps regulate cell adhesion and migration. And Yanzhuang Wang (University of Michigan) described how the E3 ubiquitin ligase HACE1 is required for the reassembly of the Golgi apparatus after mitosis. (Interestingly, HACE1 is a tumor suppressor. Is there a connection between a failure to reassemble the Golgi and tumorigenesis?)

The final two talks examined the cellular functions of ubiquitin-like molecules. Jay Debnath (UC San Francisco) spoke about Atg12, a ubiquitin-like modifier required for expanding autophagosomal membranes during macroautophagy. Debnath and colleagues found that Atg12 can be conjugated to Atg3, a protein involved in the conjugation of another ubiquitin-like protein, LC3, that is also required for autophagy. The Atg12-Atg3 conjugate isn't required for starvation-induced autophagy, however. Instead, preventing the formation of Atg12-Atg3 conjugates blocks the related pathway of mitophagy (in which mitochondria are degraded) and also inhibits mitochondrial fusion, resulting in cells with increased numbers of highly-fragmented mitochondria. Debnath thinks that Atg12 may be conjugated to several other proteins and have important functions in a number of other cellular pathways as well.

And session co-chair Frauke Melchior finished off the session with a presentation on how oxidative stress regulates the small, ubiquitin-like modifier SUMO. Sumoylation is a reversible post-translational modification that affects the function of many different proteins. Reactive oxygen species cause a reduction in the sumoylation of many target proteins. In 2006, Melchior published that ROS inhibit sumoylation by promoting the formation of a disulphide bond between catalytic cysteine residues in two enzymes required for sumoylation, blocking the activity of both proteins. Melchior now described some follow up experiments to this initial report, looking at the potential functional consequences to cells if oxidative stress fails to shut down sumoylation.

December 05, 2011

Today at ASCB, Francois Nedelec (EMBL) gave a great talk in the "Self-Organization of Cellular Structures" symposium about using the Cytosim program to model cytoskeletal dynamics. His presentation drew heavily on his JCB paper modeling the Xenopus meiotic spindle, which you can learn about in this biosights video we made to accompany the study...

December 04, 2011

On the opening day of the annual ASCB meeting in Denver, CO, I decided to check out the 'Special interest subgroup' on Rabs and Arfs - two families of small GTPases that regulate a variety of membrane trafficking events in eukaryotic cells.

Nava Segev (University of Illinois) discussed the regulation of Rab proteins (known as Ypts in budding yeast). In addition to GEFs and other factors that regulate Rab localization and activation into the GTP-bound state, Segev explained that the choice of effector protein that interacts with the active GTPase is also a critical control point that allows Rabs to function in multiple different pathways. For example, the yeast Rabs Ypt31 and Ypt32 function in both Golgi-to-plasma membrane and endosome-to-Golgi trafficking, using different effectors for each of the two pathways.

Roger Goody (MPI of Molecular Physiology, Germany) stressed the importance of GEFs in determining when and where Rabs are activated, and described how normal Rab function can be subverted by pathogens such as Legionella. Once Legionella have been internalized into a vacuole within a host cell, they secrete a number of factors that induce the recruitment of ER-derived vesicles that eventually convert the Legionella-containing vacuole into something that resembles the ER. One of these secreted factors is a protein called DrrA, which acts as a GEF that activates and recruits the host's Rab1 molecules in order to promote ER-vesicle transport to the Legionella-containing vacuole. Moreover, DrrA catalyzes the addition of an AMP-molecule onto Rab1, blocking its association with host cell regulatory and effector proteins. But AMPylated Rab1 can still interact with Legionella LidA (a 'super effector' that interacts with multiple host cell Rabs), suggesting that DrrA and LidA work together to recruit early secretory vesicles to Legionella-containing vacuoles. For a broader view of how pathogens subvert host cell membrane trafficking pathways, read this recent review from JCB. Meanwhile, Rick Kahn (Emory University) discussed the potential contribution of vesicular cargo to determining exactly where and when GEFs are prompted to activate GTPases to stimulate vesicle transport.

One recurring theme in the session was that of GTPase cascades, in which a series of Arfs and Rabs either promote or inhibit each other's activation. Arnaud Echard (Institut Pasteur, France) revealed how two GTPases that antagonize each other to ensure that cells complete cytokinesis; co-chair Elizabeth Sztul explained how one GTPase activates another to recruit different vesicle coats to the Golgi; and Sean Munro (MRC-LMB, UK) described a chain of three GTPases that act consecutively to recruit proteins to Golgi membranes.

All in all, there was plenty to ponder on from this session. With Arfs and Rabs regulating so many critical transport processes in cells, it's no wonder that their regulation is so complex. It seems that many questions remain about how cells decide exactly when and where to switch these GTPases on.

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